The present invention relates to amino acid complexes of cobalt (III) mesoporphyrin IX and cobalt (III) protoporphyrin IX useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are useful as antiobesity agents and can also be useful for treatment of cyanide poisoning, neonatal hyperbilirubinemia and cancer.
Cobalt porphyrins are known to have various endocrine activities including the regulation of food intake for controlling obesity Galbraith R. A. and Kappas A., Proc. Natl. Acad. Sci. U.S.A., 1989;86:7653-7657; Galbraith R. A. and Krey L. C., Neuroendocrinology, 1989;49:641-648; Galbraith R. A., et al., Pharmacoloy, 1987;34:241-249; Galbraith R. A. and Jellinck P. H., Biochemical and Biophysical Research Communications, 1987;145(1):376-383; Drummond G. S., et al., Proc, Natl. Acad. Sci. U.S.A., 1982;79:2384-2388; Smith T. J., et al., Pharmacology, 1986;34(9):9-16)!.
Phototherapeutic porphyrin-type dimers are disclosed in U.S. Pat. No. 4,961,920. Various porphyrins are disclosed in U.S. Pat. No. 4,393,071 to be useful in treatment of tumors; in U.S. Pat. No. 4,619,923 to control tryptophan metabolism; in U.S. Pat. No. 4,657,902 to inhibit heme metabolism; and in U.S. Pat. No. 4,782,049 to treat psoriasis. Methods of suppressing the immune system with cobalt protoporpyrins are described in U.S. Pat. No. 4,948,792; International Published Patent Application WO 87/04927 and for weight loss in International Published Patent Application WO 90/09173. The adjustment of testosterone levels in rats by the administration of cobalt mesoporphyrin is disclosed by Galbraith R. A., et al., J. Steroid Biochem., 1989;32(3):421-427. Several related cobalt porphyrins are disclosed in U.S. Pat. No. 5,149,697 and U.S. Pat. No. 5,192,757 to be antiobesity agents.
The preparations of some amino acid ester complexes with cobalt (III) deuteroporphyrin dimethyl ester and with Co(III) tetraphenylporphyrin in nonpolar organic solvents are described by Gouedard M., et al., J. Chem. Res., 1978:36-37.
We have surprisingly and unexpectedly found that common amino acid salts in water will react with cobalt (II) mesoporphyrin IX and cobalt (II) protoporphyrin to produce water-soluble complexes of cobalt (III) mesoporphyrin IX and cobalt (III) protoporphyrin IX that are effective antiobesity agents. High water solubility allows therapeutically useful dose volumes when the compounds are administered by injection. Additionally, this reduces depot effect at the injection site and has the potential for providing greater initial potency with shorter duration of action.